The present invention generally relates to an apparatus for transdermally delivering medicament ions derived from ionic substances, such as drugs or other therapeutic chemicals, into a body. More particularly, the present invention relates to an apparatus for iontophoretically introducing medicament ions into the body.
Iontophoresis may be generally described as a method of transdermally introducing medicament ions into a body. The iontophoresis process utilizes current developed by an electric field to drive medicament ions through the skin, or other biological surface, and into the body. The iontophoresis process has been found to be particularly useful in transdermal administration of medicament ions, such as charged organic medications and therapeutic metal ions.
Iontophoresis permits introduction of medicament ions directly into a patient's tissues and blood stream without the need for a needle-based injection, which typically causes pain and may create a risk of infection. Iontophoretic delivery of medicament ions also avoids premature metabolism of medicament ions that typically occurs when drugs are taken orally. Premature metabolism is of concern because medicament ions derived from drugs that are taken orally are absorbed into the blood stream from the digestive system. The blood containing the medicament ions then percolates through the liver, where the medicament ions may be prematurely metabolized, before the medicament ions arrive at the target tissue. Thus, a substantial amount of the medicament ions derived from an orally administered drug may be metabolically inactivated before the medicament ions have a chance to pharmacologically act in the body.
A typical iontophoresis device includes two electrodes. One of the electrodes is often characterized as an "active" electrode, and the other electrode is often characterized as a "return" electrode. Also, one of the electrodes is a positively charged anode and the other electrode is a negatively charged cathode. Both electrodes are in intimate electrical contact with the skin or other biological surface of the body, which may be a human body or another type of body, such as an animal body. Application of electric current to the active electrode drives the medicament ion, such as the charged organic medication, from the active electrode into the body. The other electrode, the return electrode, closes the electrical circuit to permit current flow through the active electrode and through the body.
In some cases, medicament ions may be delivered to the body from both electrodes of the iontophoresis system. In such cases, a first electrode is the active electrode for a first medicament ion that is delivered from the first electrode, and a second electrode is the return electrode with respect to the first medicament ion. Similarly, the second electrode is the active electrode for a second medicament ion that is delivered from the second electrode, and the first electrode is the return electrode with respect to the second medicament ion. The first and second medicament ions are typically different in polarity and in chemical structure from each other.
Though iontophoresis system technology has realized several advances, numerous problems remain to be solved and many opportunities for enhancing performance remain. The process of iontophoretic drug delivery may be accomplished using very simple electrodes. However, the use of more sophisticated electrode configurations is needed to solve problems that are not addressed by simple electrode systems and to realize enhanced performance characteristics. Examples of some suggested approaches for optimizing iontophoresis systems are included in U.S. Pat. Nos. 4,731,049 to Parsi; 4,915,685 to Petelenz et al.; and 5,302,172 to Sage, Jr. et al. The Parsi patent suggests a change in the iontophoresis systems that is said to increase the types of drugs deliverable by iontophoresis systems. The Petelenz patent suggests changes that are said to enhance the proportional relationship between the amount of medicament ions administered and current flow. Finally, the Sage, Jr. patent discloses the use of vasodilators in iontophoresis as a means of enhancing delivery of an active agent that is delivered along with vasodilator.
Despite the many advances in iontophoresis technology, a series of problems remain that relate to electrolysis of water in iontophoresis system electrodes. As an example, current passing through the electrodes of an iontophoresis system typically cause electrolysis of water in the electrodes. In the anode, the electrolysis reaction proceeds as follows: EQU 2H.sub.2 O.fwdarw.O.sub.2 +4H.sup.+ +4.sub.e.sup.-.
In the cathode, the electrolysis reaction proceeds as follows: EQU 2H.sub.2 O+2.sub.e.sup.- .fwdarw.H.sub.2 +2OH.sup.-.
Since an operational iontophoresis system includes both an anode and a cathode, both hydrogen ions (H.sup.+) and hydroxide ions (OH.sup.-) are produced if electrolysis of water occurs during system operation. Absent buffering of the electrolysis products, the hydrogen ion concentration will increase at the anode and the hydroxide ion concentration will increase at the cathode.
Hydrogen ion and hydroxide ion accumulation in the electrodes of iontophoresis systems is problematic for a variety of reasons. For example, the increased hydrogen ion concentration shifts the pH downward at the anode, and the increased hydroxide ion concentration shifts the pH upward at the cathode. The pH shift typically causes at least minor skin irritation and can cause severe burning of a patient's skin, if left uncontrolled. Also, the pH shift can change the activity of the medicament ion(s) being delivered by the electrode, can significantly reduce the rate of medicament ion delivery by the electrode, and can even degrade the physical properties of the electrode components.
One technique for controlling the pH shift involves the introduction of one or more buffering species into the iontophoretic electrodes. The buffering species may be in solution with the solution of the medicament ion to be delivered in the medicament delivery portion of the electrode. However, when the buffering species is in solution with the medicament ion in the medicament delivery portion of the electrode, experience has shown that the buffering species and derivatives of the buffering species undesirably compete with medicament ions for delivery to the target body.
Another technique for incorporating buffering species in iontophoresis electrodes is disclosed in U.S. Pat. No. 4,973,303 to Johnson et al. Though there are benefits to the technique disclosed in the Johnson patent, it has been found that the amount of ion-exchange functionality included in the buffer of the Johnson electrode cannot be accurately controlled. Furthermore, the Johnson technique uses several times more buffering agent than is chemically required to buffer water electrolysis products.
Though many advances in iontophoretic electrode design and operation have been realized, challenges requiring solutions remain. For example, less complicated and more accurate techniques are needed for controlling the amount of buffering species included in iontophoresis electrodes. Also, opportunities remain for enhancing the rate of medicament ion delivery by iontophoresis electrodes. Finally, opportunities remain for simplifying electrode manufacturing techniques and automating the iontophoresis electrode manufacture.